1. Field of the Invention
The present invention relates generally to the fields of cancer therapy. More particularly, it concerns the use of triterpenoid CDDO-compounds, such as CDDO and/or methyl-CDDO, in combination with other chemotherapeutic agents for the treatment of cancers.
2. Description of Related Art
Cancer has become one of the leading causes of death in the western world, second only behind heart disease. Current estimates project that one person in three in the U.S. will develop cancer, and that one person in five will die from cancer. Major challenges remain to be overcome for all cancers, but this is especially true for the hematological malignancies. For example, increasing the cure rate for acute lymphoblastic leukemia (ALL), especially for middle-aged and older adults has proved difficult. Despite high rates of complete remission, many patients relapse after chemotherapy. Chronic lymphocytic leukemia (CLL), while slow-progressing and well responding initially, frequently transforms into a drug-resistant disease.
Therapeutic regimens employed in the therapy of acute myelogenous leukemia (AML) have not changed over the last three decades and usually encompass ara-C and anthracycline analogs (Andreef, 1995). Use of new drugs such as topoisomerase inhibitors, cytokines and MDR-1 blockers have failed to impact AML patient survival (Kornblau et al., 1997; Greenberg et al., 1999; Kolitz et al., 1999; Estey et al., 1998; Beran et al., 1999). The recently synthesized new and unique triterpenoid, CDDO, has anti-proliferative effects in many human tumor cell lines (Suh, 1999), induces apoptosis in non-small cell lung cancer cells (Kim et al., 2000) and has anti-proliferative and pro-apoptotic properties in several leukemias (Konopleva et al., 1999a).
Recently, the knowledge of mechanisms controlling apoptotic pathways has increased. In general, multiple signaling pathways lead from death-triggering extracellular or intracellular signals to a central control followed by an execution stage. At this stage, CED3/caspases are activated, leading to the characteristic apoptotic structural lesions accompanying cell death which include cytoplasmic and chromatin condensation and DNA fragmentation. Two regulatory pathways have been elucidated. The death receptor pathway (also called the “extrinsic” pathway), which is triggered by members of the tumor necrosis family (TNF) family, and is mediated by recruitment of the proximal regulator caspase 8 to the death receptor complex. The activated initiator caspases in turn activate the effector caspases 3, 6 and 7. The other pathway (called the “intrinsic” pathway) involves the mitochondria and is regulated by the Bcl-2 family of proteins. In this pathway, mitochondrial sequestration or release of cytochrome C (Yang et al., 1997) is followed by the activation of Apaf-1, caspase 9, and caspase 3 (for review, see (Konopleva and Andreeff, 1999; Konopleva et al., 1998; Kornblau et al., 1999).
Most chemotherapeutic agents used in the treatment of hematological malignancies cause cell killing by inducing apoptosis. Newer approaches attempt to induce apoptosis by directly targeting apoptotic pathways. For example, agents that trigger the signaling of Fas or TRAIL receptors induce the extrinsic pathway at the cell surface. Activation of the retinoic acid receptors also results in apoptosis or differentiation via down-modulation of Bcl-2 and Bcl-XL mRNA and protein levels (Andreef et al., 1999; Agarwal and Mehta, 1997). Clinical trials of several of these agents are under way. The most striking improvement in AML therapy came with the introduction of all-trans-retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia (APL) (Castaigne et al., 1990). Early mortality of APL decreased, and over 90% of patients achieved complete remissions (Warrell et al., 1991) including some molecular remissions with PCR negativity (Estey et al., 1999). The peroxisome proliferator-activated receptor (PPAR) is a member of nuclear receptor family that is involved in apoptosis. Mutations of PPAR gene products are seen in several cancer types demonstrating the role of PPAR in cancer. Thus, PPAR based cancer therapies are another approach for anticancer chemotherapeutics.
Although some agents that target particular points of apoptotic pathways have anti-leukemic activities, none have proven optimal for treatment. There is still a need to systematically investigate new agents and to provide treatment regimens for hematological and other cancers.